The projects proposed in this mentored career development award will provide the training and experience required to reach my long term career goal to become an independent physician-scientist conducting translational research that explores the dynamic interaction between the human immune system and microbial pathogens. My career development plan combines graduate level course work with careful oversight by my co-mentors and advisory committee to ensure I am provided with the scientific background and guidance necessary to produce hypothesis driven research with rational project design, execution, and data interpretation throughout my career. The academic and scientific community of Case Western Reserve University will provide state-of-the-art environmental resources to support my career goals, as well as the necessary protected time to allow development of my skills as a physician-scientist through didactic course work, educational seminars and conferences, and pursuit of the research aims included in this proposal. The projects proposed under this application MTB directly regulates human CD4+ T cell activation introduce the hypothesis that molecules released by cells infected with Mycobacterium tuberculosis (MTB), directly interact with human CD4+ T cells leading to costimulation and upregulation of T cell activation. The preliminary data supporting this hypothesis demonstrate molecules from MTB directly upregulate human CD4+ T cell activation following T cell receptor stimulation. This interaction between MTB and human CD4+ T cells may influence the host's ability to mount an effective adaptive immune response against the pathogen. These observations suggest human CD4+ T cells utilize pattern-recognition-receptors to sense and respond to foreign material, and exploration of this hypothesis will advance the understanding of how pathogens interact with and modulate the human immune response. In addition to defining the consequences of the interaction between the identified MTB molecules and CD4+ T cells, and the receptor mediating the interaction, this project will explore if differences in CD4+ T cell responses to the identified molecules Influence host susceptibility to tuberculosis. RELEVANCE (See instructions): This research will expand the understanding of the human immune response to infection with MTB and contribute to the development of a superior MTB vaccine. By advancing knowledge of how essential components of the human immune system such as T cells interact with a foreign pathogen, this research will contribute to development of novel immunotherapies for a broad range of pathogens.